Advanced active electronic devices including collection electrodes for molecular biological analysis and diagnostics

• US 6,225,059 B1
• Filed: 01/29/1999
• Issued: 05/01/2001
• Est. Priority Date: 11/01/1993
• Status: Expired due to Term

• Current Assignee: Gamida for Life B.V.
• Original Assignee: Nanogen, Inc.
• Inventors: Ackley, Donald E., Graham, Scott O., Swanson, Paul D., Mather, Elizabeth L.
• Primary Examiner(s): Marschel, Ardin H.
• Application Number:
  US09/240,489
• Time in Patent Office: 823 Days
• Field of Search: 422/50, 422/68.1, 435/283.1, 435/285.1, 435/285.2, 435/286.1, 435/286.2, 435/287.1, 435/287.2, 435/289.1, 435/299.1, 435/303.1, 435/6
• US Class Current: 435/6.12
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 19/0093 Microreactors, e.g. miniaturised or microfabricated reactors laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/00617 by chemical means
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/00653 the compounds being bound to electrodes embedded in or on the solid supports
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00686 Automatic
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00702 Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/00713 Electrochemical synthesis
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: B01J 2219/00722 Nucleotides
• CPC Class Codes: B01J 2219/00725 : Peptides
• CPC Class Codes: B01J 2219/00731 : Saccharides
• CPC Class Codes: B01L 2200/0647 : Handling flowable solids, e.g. microscopic beads, cells, particles
• CPC Class Codes: B01L 2200/0689 : Sealing
• CPC Class Codes: B01L 2200/12 : Specific details about manufacturing devices
• CPC Class Codes: B01L 2300/0636 : Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/0645 : Electrodes
• CPC Class Codes: B01L 2300/0877 : Flow chambers
• CPC Class Codes: B01L 2300/0887 : Laminated structure
• CPC Class Codes: B01L 2400/0415 : electrical forces, e.g. electrokinetic
• CPC Class Codes: B01L 3/502715 : characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/502761 : specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: B01L 3/5085 : for multiple samples, e.g. microtitration plates
• CPC Class Codes: B82Y 10/00 : Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07B 2200/11 : Compounds covalently bound to a solid support
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07K 1/04 : on carriers C07K1/003, C07K1/006 take precedence
• CPC Class Codes: C07K 1/045 : using devices to improve synthesis, e.g. reactors, special vessels
• CPC Class Codes: C07K 1/047 : Simultaneous synthesis of different peptide species; Peptide libraries
• CPC Class Codes: C12Q 1/6813 : Hybridisation assays
• CPC Class Codes: C12Q 1/6816 : characterised by the detection means C12Q1/6804 takes precedence
• CPC Class Codes: C12Q 1/6825 : Nucleic acid detection involving sensors
• CPC Class Codes: C12Q 1/6837 : using probe arrays or probe chips C12Q1/6874 takes precedence
• CPC Class Codes: C12Q 2565/515 : characterised by the interaction between or sequential use of two or more arrays
• CPC Class Codes: C12Q 2565/607 : being a sensor, e.g. electrode
• CPC Class Codes: C40B 40/06 : Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 40/10 : Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 40/12 : Libraries containing saccharides or polysaccharides, or derivatives thereof
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: F04B 19/006 : Micropumps F04B43/043 and F04B43/095 take precedence
• CPC Class Codes: G01N 27/3276 : being a hybridisation with immobilised receptors using a FET type sensor G01N27/4145; concerning the hybridisation C12Q1/68
• CPC Class Codes: G01N 27/44743 : Introducing samples
• CPC Class Codes: G01N 33/5438 : Electrodes
• CPC Class Codes: G11C 13/0014 : comprising cells based on organic memory material
• CPC Class Codes: G11C 13/0019 : comprising bio-molecules
• CPC Class Codes: G11C 13/04 : using optical elements ; using other beam accessed elements, e.g. electron or ion beam
• CPC Class Codes: G11C 19/00 : Digital stores in which the information is moved stepwise, e.g. shift registers
• CPC Class Codes: H01L 25/50 : Multistep manufacturing processes of assemblies consisting of devices, each device being of a type provided for in group H01L27/00 or H01L29/00 H01L21/50 takes precedence
• CPC Class Codes: H01L 2924/00 : Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00
• CPC Class Codes: H01L 2924/0002 : Not covered by any one of groups H01L24/00, H01L24/00 and H01L2224/00

Abstract

Methods of manufacture and devices for performing active biological operations utilize various structures to advantageously collect and provide charged biological materials to an array of microlocations. In one embodiment, a device includes focusing electrodes to aid in the direction and transport of materials from a collection electrode to an array. Preferably, one or more intermediate transportation electrodes are utilized, most preferably of monotonically decreasing size between the collection electrode and the array, so as to reduce current density mismatches. In another aspect, a flow cell is utilized over devices to provide containment of solution containing materials to be analyzed. Preferably, the volume of the flow cell is more advantageously interrogated through use of relatively large collection and return electrodes, such as where the area of those electrodes relative to the footprint of the flowcell is at least 40%. In yet another embodiment, a first collection electrode is disposed adjacent an array, with a second collection electrode disposed on the at least an opposite portion of the array. Preferably, the combined area of the collection electrodes is a substantial fraction, preferably at least 50% of the area of the footprint of the flow cell. In yet another embodiment, a concentric ring design is provided. Various flip-chip embodiments are disclosed. A preferred embodiment utilizes a relatively small number of components, for example, five components, for a flip-chip device. A first substrate includes a via, through which solution flows to the underlying analytical chip, which a sealant between the chip and the first substrate. An overlying flow cell contains the solution. Novel manufacturing techniques are provided for utilizing the via as a shadow mask to constrain the flow of the sealant. A multiple site array system includes a row select and column select, which are preferably memory, and most preferably shift register memory. An improved current output circuit is of the current mirror type and serves to output selected current based upon input from the column select and row select.

Claims

1. An electronic device for performing biological operations comprising:

a support substrate,

an array of microlocations disposed on the substrate, the array being formed within a region,

a first collection electrode disposed on the substrate adjacent the array, the first collection electrode capable of having a charge bias, and

a second collection electrode disposed on the substrate, adjacent the array, and at least in part on the opposite side of the region, the second collection electrode capable of having a charge bias,

wherein the first collection electrode has an area at least 80% of the area of the region.

2. The electronic device for performing biological operations of claim 1 wherein the first collection electrode and second collection electrode are disposed at substantially opposite ends.

3. The electronic device for performing biological operations of claim 1 further including a flow cell, the flow cell adapted to be supported on the substrate and to define a footprint of the flow cell.

4. The electronic device for performing biological operations of claim 3 wherein the first collection electrode and second collection electrode are disposed at substantially opposite ends of the footprint of the flow cell.

5. The electronic device for performing biological operations of claim 1 wherein the first collection electrode has an area at least 100% of the area of the region.

6. The electronic device for performing biological operations of claim 1 wherein the first collection electrode has an area at least 120% of the area of the region.

7. The electronic device for performing active biological operations of claim 1 further including capture sequences.

8. The electronic device for performing active biological operations of claim 7 wherein the capture sequences are disposed adjacent the collection electrode.

9. The electronic device for performing active biological operations of claim 1 wherein the collection electrode is a complexity reduction electrode.

10. The electronic device for performing active biological operations of claim 1 further including focusing electrodes.

11. The electronic device for performing active biological operations of claim 3 wherein the area of the first collection electrode and second collection electrode in proportion to the footprint of the flow cell is at least 40%.

12. The electronic device for performing active biological operations of claim 3 wherein the area of the first collection electrode and second collection electrodes in proportion to the footprint of the flow cell is at least 50%.

13. The electronic device for performing active biological operations of claim 3 wherein the area of the first collection electrode and second collection electrodes in proportion to the footprint of the flow cell is at least 60%.

14. The electronic device for performing active biological operations of claim 3 wherein the flow cell includes an inlet.

15. The electronic device for performing active biological operations of claim 3 wherein the flow cell includes an outlet.

16. The electronic device for performing active biological operations of claim 1 wherein the first collection electrode and the second collection electrode are of the same size.

17. The electronic device for performing active biological operations of claim 1 wherein the first collection electrode and the second collection electrode are of the different sizes.

18. The electronic device for performing active biological operations of claim 17 wherein the first collection electrode has an area smaller than the area of the second electrode.

19. The electronic device for performing active biological operations of claim 17 wherein the first collection electrode has an area at least substantially 10% smaller than the area of the second collection electrode.

20. The electronic device for performing active biological operations of claim 1 wherein the first collection electrode is a trapezoid in shape.

21. The electronic device for performing active biological operations of claims 1 or 20 wherein the second collection electrode is a trapezoid in shape.

22. The electronic device for performing active biological operations of claim 20 wherein the trapezoid has a base adjacent the array and a top disposed away from the array and the base is longer than the top.

23. A method for analysis of a biological sample, utilizing the electronic device for performing active biological operations of claim 1, comprising the steps of:

providing the sample to the device,

placing the first collection electrode attractive for desired charged biological materials, thereby concentrating charged biological materials on the collection electrode,

placing the second collection electrode attractive for the desired charged biological materials, relative to the first collection electrode, thereby transporting said charged biological materials from the first collection electrode towards the second collection electrode, and over at least a portion of said array of microlocations disposed on the substrate, whereby interaction between the charged biological materials and the array occurs.

24. The method for analysis of a biological sample of claim 23 utilizing an electronic device for performing active biological operations, wherein the array is maintained electrically passive.

25. The method for analysis of a biological sample of claim 23 utilizing an electronic device for performing active biological operations, wherein the array is electrically active to facilitate interaction between the array and the charged biological material.

26. The method for analysis of a biological sample of claim 23 utilizing an electronic device for performing active biological operations, wherein the charged biological material is moved over the array as a wave.

27. The method for analysis of a biological sample of claim 23 utilizing an electronic device for performing active biological operations, wherein the charged biological material is moved over the array.

28. The method for analysis of a biological sample of claim 23 utilizing an electronic device for performing active biological operations, wherein the charged biological material is moved over the array and maintained in that lateral position relative to the substrate.

37. The electronic device for performing biological operation of claim 1, wherein the array of microlocations comprises an analytical chip.

38. The electronic device for performing biological operation of claim 1, wherein the array of microlocations comprises an active programmable electronic matrix.

29. An electronic device for performing active biological operations comprising:

a support substrate,

an array of microlocations disposed on the substrate,

a counter electrode disposed on the substrate surrounding the array, the counter electrode capable of having a charge bias, and

a first collection electrode disposed on the substrate and disposed interior of the array, the first collection electrode capable of having a charge bias.

30. The electronic device for performing active biological operations of claim 29 wherein the first collection electrode is segmented.

31. The electronic device for performing active biological operations of claim 29 wherein multiple rings are provided surrounding the array.

32. The electronic device for performing active biological operations of claim 29 further including capture sequences.

33. The electronic device for performing active biological operations of claim 32 wherein the capture sequences are disposed adjacent the collection electrode.

34. The electronic device for performing active biological operations of claim 32 wherein the collection electrode is a complexity reduction electrode.

35. The electronic device for performing active biological operations of claim 29 wherein the microlocations are arranged in a circular manner.

39. A method for analysis of biological sample, utilizing the electronic device for performing active biological operation of claim 29, comprising the steps of:

providing the sample to the device,

placing the first collection electrode attractive for desired charged biological materials, and

placing the counter electrode having an opposite charge with respect to the charge of the collection electrode, thereby concentrating the desired biological materials at the collection electrode, and transporting said charged biological materials over at least a portion of the array of microlocations disposed on the substrate.

40. The method for analysis of biological sample of claim 39 utilizing an electronic device for performing active biological operations, wherein the array is maintained electrically passive.

41. The method for analysis of biological sample of claim 39 utilizing an electronic device for performing active biological operations, wherein the array is maintained electrically active to facilitate interaction between the array and the charged biological materials.

42. The method for analysis of biological sample of claim 39 utilizing an electronic device for performing active biological operations, wherein the charged biological material is moved over the array as a wave.

43. The method for analysis of biological sample of claim 39 utilizing an electronic device for performing active biological operations, wherein the charged biological material is moved over or positioned above the array.

36. An electronic device for performing active biological operations including:

a substrate,

a flowcell adapted to contain fluids containing biological materials, said flowcell being supported by said substrate, the flowcell defining a footprint on said substrate, and

a plurality of electrodes disposed on said substrate, said electrodes including at least a return electrode and a collection electrode, the return electrode and collection electrode being positioned at the periphery of the flowcell footprint so as to interrogate substantially all of the volume of the flowcell.

44. An electronic device for performing biological operation comprising:

a support substrate;

an array of microlocations disposed on the substrate, the array formed within a region;

a flow cell adapted to be supported on the substrate and define a footprint of the flow cell; and

a collection electrode disposed on the substrate proximal to the footprint, the collection electrode capable of having a charge bias

wherein the collection electrode has an area at least 80% of the area of the region.

45. The electronic device of claim 44, wherein the collection electrode is disposed adjacent the array.

46. The electronic device of claim 45, further comprising a second collection electrode disposed on the substrate, adjacent the array, and at least in part opposite side of the region.

47. The electronic device of claim 46, wherein the first collection electrode and second collection electrode are disposed at substantially opposite ends.

48. The electronic device of claim 45, further comprising a return electrode disposed on the substrate.

49. The electronic device of claim 44, further comprising:

one or more focusing electrodes disposed on the substrate, the focusing electrodes being disposed at least in part adjacent the array of microlocations, and

a counter electrode disposed on the substrate.

50. The electronic device of claim 49, further comprising one or more transport electrodes, the one or more transport electrode being disposed on the substrate and positioned between the collection electrode and the array.

51. The electronic device of claim 44, wherein the collection electrode is larger than the region defined by the array of microlocations.

52. A electronic device for performing biological operations comprising:

a support substrate,

an array of microlocations concentrically disposed on the substrate,

a concentration electrode disposed on the substrate and disposed interior of the array, and

a return electrode concentrically disposed on the substrate surrounding the array, wherein the location of the array of microlocations is concentric with respect to the concentration electrode and, whereby the return electrode and the collection electrode co-act to concentrate the desired biological material at the concentration electrode and then to move it over or position it above the array.